Frontier: Fine-tuning mechanism may hold key to Alzheimer’s disease.

Major suspects in Alzheimer’s disease are also players in a normal brain-sculpting process, according to a study in the Feb. 19 Nature. A pathway active during development may reactivate later in life to cause the disease.

In Alzheimer’s disease, neurons die off and beta-amyloid protein fragments collect into sticky plaques. The protein from which the fragment derives, amyloid precursor protein (APP), contributes to the disease, but its role has remained unclear.

Marc Tessier-Lavigne and colleagues at Genentech Inc. in San Francisco and the Salk Institute in La Jolla, Calif., were exploring how the embryonic brain prunes away unwanted connections. They focused on the ominously named Death Receptor 6 (DR6), which is plentiful in developing neurons. Neurons self-destruct in response to many signals, such as loss of protective “trophic factors.” The researchers suspected DR6 was involved.

In cultured neurons and mice lacking DR6, the team showed that neurons deprived of trophic factors live longer if DR6 is blocked or missing—implicating this receptor in the self-destruct mechanism. The next challenge: to find the activating molecule, or ligand.

“The signal for the neuron to kill itself had to be kept in check until the proper time,” says Tessier-Lavigne. “When we realized APP filled the bill for being the ligand, we almost fell off our chairs.”

The study shows that removal of trophic factors activates the enzyme beta-secretase (which helps form the plaques of Alzheimer’s disease). This enzyme chops APP into a fragment that binds to DR6 to trigger neuronal self-destruction.

Both DR6 and APP are more prevalent in areas of the brain affected by Alzheimer’s compared with areas that are not—guilt by association, according to Tessier-Lavigne.

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